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Patience is a Virtue for Combination Product ManufacturersBy Marci Crane

In a very real sense combination product manufacturers are changing the face of life science research and manufacturing. In fact, the near future may paint the combination products sector as the leading life science industry sector, while products like transdermal patches for depression, dental bone grafting material with a growth factor, absorbable collagen sponges with genetically engineered human protein, or a surgical mesh with antibiotic coating may become more common than their "less complete" components.

A Work in Progress In the meantime however, combination products are a work in progress, not unlike their regulatory parent, the FDA's Office of Combination Products (OCP). The OCP organization--although small--is growing because a need for (and an interest in) combination products is increasing. On the other hand however, the OCP has also undergone recent changes that will require that combination product manufacturers practice patience...and plenty of it.

Why so slow? The OCP is causing combination product manufacturers a bit of angst. After all, the last GMP combination product guidance release is already four years old and is only a draft. It's no wonder that combination product manufacturers are looking for more input and direction. Some manufacturers were even expecting an official guidance this spring (2008) but are unlikely to see it--at least according to FDANews which states the following:

"Organizational changes at the FDA's Office of Combination Products (OCP) are expected to slow the issuance of guidance documents and regulations for combination products, according to an industry consultant."1 These organizational changes announced by the FDA seem to primarily indicate intense changes in the area of OCP staffing. Michael Gross, of Chimera Consulting says that "There's almost a completely new staff. ... They are going to be on a steep learning curve, and unfortunately progress is going to be slow for a while..."2

Even attorney Jim Cohen is now no longer an OCP member, and it was Cohen who worked to create a GMP rule for manufacturers of combination products. Mark Kramer, the OCP's director has also been replaced by incumbent Thinh Nguyen.

In response to an inquiry regarding the need for the staff changes at the OCP, Thinh Nguyen states that "Over the past year, three key staff members (out of 8) including the OCP Director left OCP to pursue other opportunities, both inside and outside of FDA. In order to continue the work that OCP is mandated to do by Congress, it was necessary to replace the previous staff members with new staff members with similar scientific and regulatory expertise."

In regard to the necessity of these changes and the benefits they will provide for life science companies, Nguyen also states the following:

"These changes are necessary in order for OCP to continue to serve as resource for the regulated industry and FDA staff with regard to combination products issues. Specifically, the staff changes will enable OCP to continue to develop policies, guidance documents and regulations, answer regulatory and scientific questions from FDA staff and regulated industry, present FDA's views at industry workshops and meetings, make jurisdictional determinations, oversee and coordinate premarket reviews, and also ensuring consistent post-market regulations of combination products."

Despite the necessary changes at the OCP, the forecast for the upcoming GMP rule may reach promulgation earlier than expected. FDANews states that "Despite the personnel losses at the OCP, Gross still expects the FDA to release the GMP rule this year — just not in the spring when it was expected."3

What else will the OCP accomplish? There are other factors that may contribute to the slow down at the OCP. A lengthy to-do list might be one of those factors. In a report4 that the OCP brought to Congress, the OCP's projects and activities included the following:

In the Meantime Obviously the OCP is under pressure, but there are additional measures (besides waiting for the planned product guidance) that combination product manufacturers can do to improve their chances of getting quality and compliance right the first time around. Here are just a few:

Invest in Streamlined Technologies Since combination product manufacturers are juggling guidance documents released by CBER, CDER and/or CDRH as well as requirements stipulated by a host of worldwide regulatory bodies, compliance can be painstakingly tedious, frustrating and expensive. Maintaining compliance and reasonable compliance costs with automated software technology sounds like the perfect solution but combination product manufacturers may find it pointless to turn to automated technologies that are designed with "discrete-only" or "process-only" manufacturers in mind. Combination product manufacturers need to know that there are software solutions available that can streamline document control, change control, audits, CAPAs, customer complaints management, deviations management and training for both discrete and process manufacturing sectors. Combination product manufacturers should search for these types of solutions and ensure that they can be utilized within one combined system.

Invest in Training In recent years, the FDA's focus has turned towards a Quality by Design (QbD) initiative, which encourages less process testing and more assurance of error free pre-manufacturing design. The initiation of Quality by Design techniques and processes is likely to require continuous training for both quality and compliance related topics such as PAT (Process Analytical Technology) controls. In regard to PAT the FDA websites states the following:

"The goal of PAT is to understand and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design,"6 and

"A desired goal of the PAT framework is to design and develop processes that can consistently ensure a predefined quality at the end of the manufacturing process. Such procedures would be consistent with the basic tenet of quality by design and could reduce risks to quality and regulatory concerns while improving efficiency."7

Invest in Risk Assessment Practices Like QbD practices, risk assessment practices require a lot of pre-product planning. Whether it is for human use factor analysis or risk assessment practices during design and product manufacturing, these processes must be well planned and supported by deviations and nonconformance trending, reporting and analysis as well as a definite CAPA process. As mentioned above these types of processes can be streamlined with the appropriate technologies.

The QMS Provider for the FDA

MasterControl Inc. and its partner, i4DM, are expanding their FDA project, serving as the QMS providers for a second FDA division. The two companies have been the QMS providers for the FDA's Office of Regulatory Affairs since 2009. Now they will also serve as quality providers for the Division of Pharmaceutical Analysis, which is part of the FDA's Center for Drug Evaluation and Research.

Software Magazine ranks MasterControl 369 on its 2014 Software 500 list, a listing of the world's largest software and services providers. Now in its 32nd year, the Software 500 is a revenue-based ranking of vendor viability. Learn More